CN107669681A - Pharmaceutical preparation containing dihydrohydroxycodeinone and naloxone - Google Patents

Pharmaceutical preparation containing dihydrohydroxycodeinone and naloxone Download PDF

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Publication number
CN107669681A
CN107669681A CN201710521042.3A CN201710521042A CN107669681A CN 107669681 A CN107669681 A CN 107669681A CN 201710521042 A CN201710521042 A CN 201710521042A CN 107669681 A CN107669681 A CN 107669681A
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China
Prior art keywords
preparation
naloxone
dihydrohydroxycodeinone
release
officinal salt
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Inventor
比安卡.布罗格曼
西尔克.米劳
克里斯托弗.斯皮茨利
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Euro Celtique SA
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Euro Celtique SA
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Priority claimed from DE10215067A external-priority patent/DE10215067A1/en
Priority claimed from DE10215131A external-priority patent/DE10215131A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Abstract

The present invention is on a kind of bin stability pharmaceutical preparation of dihydrohydroxycodeinone and naloxone containing for treating pain, it is characterised in that reactive compound is to be discharged in a manner of lasting, stable and independent from said preparation.

Description

Pharmaceutical preparation containing dihydrohydroxycodeinone and naloxone
The application is the applying date on April 4th, 2003, Application No. 201210216908.7, entitled " containing hydroxyl Hydrogen can treat the pharmaceutical preparation of ketone and naloxone " application for a patent for invention divisional application.
Technical field
The present invention relates to one kind containing dihydrohydroxycodeinone (oxycodone) and naloxone (be also naloxone, Naloxone the pharmaceutical preparation of storage stabilization).
Background technology
Severe pain caused by the diseases such as treating cancer, rheumatism and arthritis is the core for treating these diseases.Tumour The pain dimensions that patient is experienced include pain periosteum and bone in itself, and splanchnodynia and soft tissue pain.It is all such Pain causes patient's daily life to be difficult to endure and frequently result in depressive state.Therefore, quality of life of patients can be allowed persistently to improve Successful pain therapy is heavy on an equal basis with the success of composite treatment (this therapy is that the actual cause of disease for being directed to the disease is treated) Will.
Importance about success pain therapy, the World Health Organization (WHO) have developed treatment relaxing tumor pain patient Four steps pattern.This pattern has proven to effectively in regular job, and may extend to the patient with chronic ache, Or the patient with the types of pain caused by the disease beyond cancer.According to the intensity, property and position of pain, this therapy mistake Cheng Zhongke distinguishes four steps, and until the effect of used pain relief medication is no longer enough, then needs next step (Ebell.H.J.；Bayer A.(Ed.):Die Schmerzbehandlung von Tmuorpatienten,Thieme 1994 (Supportive Ma β nahmen in der Onkologie, Band 3) and Zech, D.；Grond,S.；Lynch, J.；Hertel,D.；Lehmann,K.：Validation of World Health Organisation Guidelines for Cancer Pain Relief:a 10-year prospective study,Pain(1995),63,65-76)。
According to WHO this four steps pattern, class opium (opioid) anodyne plays core angle in treatment pain Color.In addition to representing the morphine of this pharmaceutical active medicament prototype, class opioid analgesic also includes dihydrohydroxycodeinone, dihydro Coffee ketone (hydromorphone), gewalan (nicomorphine), paracodin (dihydrocodeine), Hai Luo Because of (diamorphine), Papaveretum (papaveretum), codeine, dionin, Phenylpiperidine and its derivative；It is U.S. husky Ketone (methadone), dextropropoxyphene (dextropropoxyphene), BUP (buprenorphine), pentazocine (pentazocine), tilidine (tilidine), C16H25NO2 (tramadol) and dihydrocodeinone (hydrocodone). WHO ATC classification (anatomy treatment chemical classification) indicates whether a pharmaceutical active agent represents a kind of opioid analgesic. The notable pain relief effect of class opioid analgesic is due to simulation endogenous, morphine sample working substance (endogenous opiate sample thing Matter) effect caused by, the physiologic function of the endogenous morphine sample working substance is the reception and processing that control pain stimulates.
The diffusion that class opium inhibition of pain stimulates.Except constraining immediately in spinal cord as the neuronal excitation caused by class opium Outside property message conduction, a kind of from brain bar to launch nerve pathway activation to spinal cord also relevant.This activation The pain diffusion phenomena in spinal cord are caused to be suppressed.Furthermore class opium limitation thalamus receives pain, and by limbic system (limbic sytem) has an effect and influences the evaluation of emotionality pain.
Opioid receptor can be found in internal diverse location.The acceptor of intestines and brain to by opioid pain therapy especially It is important, particularly when these acceptors are occupied and cause different side effects.
If class opioid analgesic is pressed down strongly with the reception that high affinity is bound to opioid receptor and lures pain into System, then such opioid analgesic is considered as potent activator.Combined with high affinity with opioid receptor but do not cause pain to connect Receive to reduce and be designed to antagonist so as to the material of antagonism OPIOIDS activator.According to bonding behavior and the activity induced, class Opium can be categorized as simple activator, mixed type agonist/antagonist and pure antagonistic agent.For example, pure antagonistic agent bag Include such as naltrexone (naltrexone), naloxone (naloxone), nalmefene (nalmefene), nalorphine (nalorphine), nalbuphine (nalbuphine), naloxone love new (naloxoneazinen), methyl naltrexone (methylnaltrexone), Kai Disaixin (ketylcyclazocine), Ruo Binnafenming (norbbinaltorphimine), naltrindol (naltrindol), 6- β-receive leading (naloxol) and 6- β-receive head of quenching (naltrexol)(Forth W.,；Henschler,D.；Rummel W.；Starke,K.:Allgemeine und Spezielle Pharmakologie und Toxikologie,7.Auflage,1996,Spetrum Akademischer Verlag,Heidelberg Berlin Oxford)。
Due to its compound such as good analgesic efficacy, dihydrohydroxycodeinone, tilidine, BUP and pentazocine already with Treat the medicament forms of pain and use.Such as(wherein hydroxyl hydrogen codeine be analgesic activity compound) and(wherein tilidine be analgesic activity compound) etc. medicine have confirmed to treatment pain it is effective.
May be in the lump along with undesirable side effect however, treating pain using class opioid analgesic.It is therefore long-term use of Class opioid analgesic can cause psychology and physical dependence.
Particularly developing for drug resistance can be caused for the physical dependence of class opioid analgesic by the bitter patient of pain, This means along with long-term intake medicine, patient is for pain relief to be obtained, the then agent of raising pain relief medication gradually Amount.Class opioid analgesic makes us the buoyant abuse for acting on and often resulting in pain relief medication.Drug abuse and psychology according to Bad property is common phenomenon, is occurred especially between teenager.These dangerous influences are especially by the thing of potent analgesic ability Caused by matter, coverage by undesirable custom to it is fully developed be habituation.But these materials are legally to be used in doctor Treat in purposes, and can not be without these materials in medicine.
In addition to the shortcomings described above, following undesirable secondary work is generally also resulted in using class opioid analgesic treatment pain With：Such as intractable constipation, respiratory depression (breath depression), vomiting and calmness.Not being frequently observed is, compels Being essential will drink water or can not drink water.Completed it is various trial come resist addicted process betide in pain therapy other pair make With.This kind of trial is caused using the methods of such as traditional treatment.For drug habit, medicine can be attempted and stop therapy；Just For intractable constipation, logical purgatives can be applied.
Other attempt to pass through the antagonist applied and resist such opioid analgesic, and its object is to by addicted and habit formation Tendency and other side effects are reduced to minimum.This kind of antagonist can be naltrexone or naloxone.
Undesirable habit formation and dependence are avoided that relating to how to apply above-mentioned reactive compound at present, or even Habituation has had many suggestions and teaching.
United States Patent (USP) US 3,773,955 and 3,966,940 suggests, when parenteral, promotes to prevent dependence Effect is such as happy, by anodyne and naltrexone combination preparation.So far method there is no to avoid the side effects such as intractable constipation.
In order to limit the parenteral of oral administration form abuse, United States Patent (USP) US 4,457,933 suggests morphine and song of receiving Ketone combines in the range of given dose.The patent does not refer to how avoiding the side effects such as intractable constipation yet.
For the purposes of avoiding abusing, it is not parenteral administration or sublingual administration that United States Patent (USP) US 4,582,835, which describes one kind, Preparation, it contains the combination of BUP and naltrexone.
The A1 of German patent application DE 0 352 361 are related to be controlled by oral class opioid analgesic with antagonist for treating pain Intractable constipation during treatment, the antagonist are the prodrug forms of naltrexone or naloxone.Avoid the indiscriminate of class opioid analgesic With the emphasis of not this application case.
The A1 of German patent application DE 43 25 465 are directed to control using the preparation containing class opioid analgesic and antagonist Treat the intractable constipation during pain therapy.The case disclose technical characteristic be：Antagonist (can be allyl hydrocarbon hydromorphone) Dosage must be higher than the dosage of class opioid analgesic (preferably morphine).This is in order to ensure antagonist can show anti-stubbornness The effect of property constipation, but the analgesic activity of activator is not reduced.The abuse for avoiding class opioid analgesic is not the weight of this application case Point.
For the side effect during pain therapy to be avoided, such as intractable constipation and respiration inhibition, on the market Import can oral administration preparation, it contains class opioid analgesic and class opiate antagonists (naloxone).Windrop/ The medicine of Sterling companiesContain pentazocine and naloxone.The medicine of Godeke companiesContain The combination of tilidine-naloxone.
Except strong analgesic efficacy, reduce habituation possibility and in addition to avoiding side effect, suitable for pain therapy medicine also More features should be provided.
In general, medicine must be formulated into reactive compound mode as stable as possible under the conditions of typical shelf.Medicine Thing also must be formulated into what the predetermined release mode of reactive compound (release profiles) did not changed with long-term store Form.
Furthermore the release mode of (equally also in the combination of agonist/antagonist) each single-activity compound Be able to should optionally it select.In order to reach this purpose, used measure should not obstruct, even prevent other active ingredients Thing (for example, with regard to different activities compound combination when) release mode.Therefore, release mode should not have interdependency.
Suitable for pain therapy medicine should the dosage containing reactive compound be patient only on rare occasions It must take, or should be allocated in a manner of patient only just must take the medicine on rare occasions.Pain relief agents Medication flow it is simpler, patient more can grasp which tablet why it and should should take with more high-frequencies, then patient More can be really in accordance with the order of doctor.Simply just there is the necessity for taking pain relief agents once in a while, clothes for patients will be caused with the pain The wish of agent for releasing is high (biddability).
Once attempted via use so-called sustained release preparation (that is, medicine of the reactive compound with long-time from insoluble drug release Preparation) come reduce analgesic drug product must medication frequency, thereby increase patient biddability.This sustained release preparation also causes " class The sustained release of opioid analgesic can reduce the habituation possibility of the reactive compound " thing understood.
Because the habituation possibility of reactive compound is not determined in itself by the compound, but by applying the compound Depending on mode and resulting pharmacodynamics.In addition to opioid rush mentation, frequency that brain contacts with class opium, than The reactive compound itself, even more produces decisive indicator (Nolte, the T. of dependence risk:STK-Zeitschrift fur angewandte Schmerztherapie,2001,Vol.2)。
The medicine of Purdue companiesIt is the system that class opioid analgesic dihydrohydroxycodeinone is discharged with continuous fashion Agent.Due to such a formula, it is necessary to which the frequency and addicted possibility for taking the medicine reduce, but side effect still suffers from, and can not The danger of development habituation is excluded, becauseClass opiate antagonists are not contained.
According to the previously mentioned A of european patent application EP 0 352 361, class opioid analgesic or antagonist are not all matched somebody with somebody It is made and is discharged with continuous fashion.So the time of kind preparation energy useful effect is restricted, and said preparation must be daily using more It is secondary, it is unable to reach desired patient's biddability.The advantages of being also formulated in this patent application case without announcement said preparation is with work Property compound through when stable and independent release be characterized.The bin stability of said preparation is not recorded in the technology contents of the case yet In.
What the A1 of German patent application DE 43 25 465 were disclosed matches somebody with somebody the intractable that can prevent to occur during pain therapy Constipation, it is to utilize sustained release class opioid analgesic, and antagonist existing for excess then can not necessarily be discharged with continuous fashion.By In the high first pass effect of naloxone, it is therefore necessary to use a considerable amount of compound.This patent application case does not disclose system The advantages of agent, the also formula without said preparation, said preparation be by active compound through when stable and independent release characterized by.This kind of system The bin stability of agent is not the emphasis of the case technology contents.Therefore doctor according to this case technology contents and use preparation when, every time When he thinks incremental dose, substantial amounts of titration experiments must be just carried out.
Godeke companies provide trade namePain relief agents, it contains the group of tilidine-naloxone Close.According to the description of product, it is to match somebody with somebody two kinds of reactive compounds can be allowed to discharge with continuous fashion using one kind.Used matrix Water expandable substance (HPMC) including proper proportion, therefore the matrix is considered as a kind of inflatable (may have partial corrosion) Diffusion matrix (diffusion matrix).The shortcomings that such a known formulations is that tilidine and naloxone are to give identical matter Ratio is measured, but absolute content is different, therefore different release modes can be presented in two kinds of compounds.The rate of release of activator and antagonist It is independent mutually, it may be possible to caused by used Sustained-release formulations.Therefore, if doctor wants incremental dose, even if not changing Become tilidine：During the quality ratio of naloxone, because he can not determine that the release mode of two kinds of components will remain unchanged as, doctor is necessary A large amount of titration experiments are carried out for each individual patient.Therefore, doctor is for useful in the adoptable treatment of the anodyne Dosage range is restricted.
The content of the invention
An object of the present invention is to provide a kind of pharmaceutical preparation for pain therapy with high analgesic activity, and it is special Sign is to reduce abuse potential and side effect, and said preparation is also characterized by medicine frequency reduces, therefore said preparation also provides more The ability of high biddability and every patient's individual adaptation dosage.Another object of the present invention is to provide in pain therapy The formula of effective pharmaceutical preparation, it ensures that the reactive compound of the pharmaceutical preparation is still stable during undergoing one section of long storage , and even across long-term storage after, the release of the reactive compound reproducibly keeps constant and independent.
The combinations of features of this case independent claims can realize object of the present invention, and other objects of the present invention can Referring to the description of the present invention.The preferred embodiments of the invention are then defined in dependent claims.
According to the present invention, its purpose is by providing a kind of bin stability medicine system containing dihydrohydroxycodeinone and naloxone Agent and reach, wherein said preparation allotment be made reactive compound to continue, it is stable and independent in a manner of discharge.
Pass through the combination of dihydrohydroxycodeinone (the effective amount of analgesic) and naloxone, it is ensured that preparation of the invention presents effective Analgesic activity, while suppress or at least significantly reduce common side effect, such as intractable constipation, respiratory depression and develop into Addiction.Matrix formulations steady in a long-term can chronically ensure that activator is always discharged with antagonist with percentage set in advance, and Its rate of release is not interfere with each other each other.In this way, preventing the abuse of the medicine, the abuse needs dihydrohydroxycodeinone certainly can should Extract to formulation selection.According to the formula of the present invention cause activator can not the never antagonist of corresponding amount preparation Optionally extract, this is unrelated with the absolute and relative amount of antagonist with selected activator.
Furthermore ensure that the same release can be presented in the same reactive compound of relative amount according to the formula of the medicine of the present invention Mode playback, it is unrelated with absolute content.When optimal agonist/antagonist ratio for it is known when, then such a independent release behavior Analgesic active workable absolute dosages on a large scale are provided to doctor.Therefore, each other patient is possible to easypro Clothes adjust dosage comfortablely, are stepped up dosage, or if necessary, gradually reduce dosage.It is indivedual to suffer from for medical viewpoint It is extremely useful that person, which has the ability of adjustable dosage,.
The technical characteristic of the present invention, including persistently, stably and independently release of active compounds, can more ensure according to this hair Bright produced pharmaceutical preparation is low for its feature with medicine frequency, therefore can reach the patient compliance of height.In addition, this hair Bright preparation allows doctor to adjust dosage for few patients.The preparation of the present invention ensures that large-scale reactive compound can be used The absolute dosages being applicable, and ensure that reactive compound can still recover effect after long-term storage and have identical to release Mode playback.
According to the present invention, the sustained release of reactive compound refers to the time that pharmaceutically active substances are undergone from insoluble drug release It is longer by the time discharged for the known formulations of quick release than the material.It is preferred that release undergoes 2 to 24 hours, 2 to 20 Hour, more preferably after 2 to 16 hours or 2 to 12 hours, this is according to the explanation in accordance with law and control requirement.
In accordance with the invention it is possible to ensure reactive compound self-preparing agent it is as described above as the pharmaceutical formulation of sustained release be referred to as Retardance ((retard) formula, Sustained-release formulations or sustained release (prolonged release) formula.The technology contents of the present invention In, " sustained release " be not offered as reactive compound from be formulated or insoluble drug release be in a manner of pH- dependences.According to the present invention, The release of reactive compound is in a manner of independent of pH.According to the present invention, " sustained release " one word is to represent reactive compound After long-time from insoluble drug release.This is not meant in a certain ad-hoc location control release, therefore is not offered as the active ingredient Thing only discharges in stomach, or is only discharged in enteron aisle.(certain such a release in ad-hoc location can pass through the enteric coating of medicine respectively Realize, but such a mode seems to have no benefit at present.)
According to the present invention, " independent release " refers to assume two kinds of reactive compounds at least be present, changes a kind of compound Absolute content has no effect on the release mode of another compound, therefore the release mode of another compound does not change.According to this hair Bright formula, pH value, target or preparation method of such a independent release behavior independent of measurement release.PH independence especially should For acid range, i.e. pH value is less than 7.Release mode (or release behavior) is defined as reactive compound and discharged at any time from formula Between, the change of the amount (being represented with accounting for the percentage of reactive compound total amount) of each reactive compound that is discharged.Discharge mould The measure of formula is to utilize known method of testing.
In detail, such as by taking the release mode of second dihydrohydroxycodeinone as an example, if containing in the corresponding preparation with same recipe There are 12mg dihydrohydroxycodeinones but contain 6mg naloxones, then can find that there is the hydroxyl hydrogen of 12mg dihydrohydroxycodeinones and 4mg naloxones It can treat that ketone/naloxone-combination does not change the release mode of second dihydrohydroxycodeinone.
The feature independently discharged is preferably directed to a kind of by the ratio of release mode work one with the preparation for being substantially equal composition Compared with situation.With reactive compound of the preparation with different content for being substantially equal composition, but substantially influence release row For combination component be substantially identical.
If (the first preparation contains 12mg dihydrohydroxycodeinones and 4mg naloxones to more above-mentioned preparation, and the second preparation contains 12mg Dihydrohydroxycodeinone and 6mg naloxones), it is assumed that the gross weight of two kinds of preparations is identical, matches somebody with somebody if the difference of naloxone content is substituted by It is a kind of generally when not interfering with composition part of release behavior in side, then it will obtain the release of identical dihydrohydroxycodeinone and naloxone Pattern.Shown in following article embodiment part, the content difference of naloxone can be substituted by a typical pharmaceutical inert filler, example Such as lactose, this substitution does not change release mode.
One skilled in the art will appreciate that if the difference of two kinds of preparations is the content of reactive compound, by the compound Necessary to content is substituted by the release behavior of the formula during material, such as ethyl cellulose or fatty alcohol, release row can be produced For difference.Therefore, independent release characteristic is preferably applied in following formula, and it has the reactive compound of different content, and real It is identical or at least highly similar (formula with identical gross weight is compared in setting) that composition part of release behavior is influenceed in matter.
According to the present invention, " stable release behavior " or " stable release mode " is if be defined as absolute content change, per unit The absolute content percentage unobvious for each reactive compound that time is discharged change and fully keep constant (former unreal Change in matter).Fully constant percentage refers to that the difference of percentage that time per unit discharged and average value is no more than 20%, preferably more than 15%, more preferably no more than 10%.Average value is calculated by six measured values of release mode 's.Certainly, the burst size of time per unit has to comply with law and control requirement.
In detail, Lip river is received if setting a kind of combination of dihydrohydroxycodeinone/naloxone and containing 12mg dihydrohydroxycodeinones and 4mg Ketone, in the dihydrohydroxycodeinone and 20% naloxone of initial release 25% in 4 hours.If the group of the dihydrohydroxycodeinone/naloxone Conjunction contains 24mg dihydrohydroxycodeinones and 8mg naloxones, and 25% dihydrohydroxycodeinone was also discharged in initial 4 hours and 20% receives Lip river Ketone.In two kinds of situations, difference all by no more than the 20% of average value (dihydrohydroxycodeinone that the average value of this example is 25% and 20% naloxone).
As briefly described independent release behavior, stable release characteristic is substantially equal composition it is also preferred that referring to one kind and will have The release mode of preparation make the situation that compares.The active compound content of this kind of preparation is different, but just influences the system of release For agent component, the composition of this kind of preparation is identical or at least highly similar.Typically, the content difference of reactive compound will be with reality The pharmaceutical inert excipient substitution of the release behavior of said preparation is not influenceed in matter.This kind of pharmaceutical excipient can be lactose, and it is Typical fillers in pharmaceutical preparation.Those skilled in the art will fully understand that this stable release characteristic can not be applied in following system The known substance that the difference of agent, wherein active compound content is substantially influenceed said preparation release behavior substitutes, such as ethyl Cellulose or fatty alcohol.
If it is stated that a preparation contains 20mg dihydrohydroxycodeinones and 1mg naloxones or contains 20mg in embodiment part Dihydrohydroxycodeinone and 10mg naloxones, its difference are that naloxone is substituted by lactose, two kinds of preparations so with identical weight Identical release mode is provided, therefore lasting, stable and independent release behavior is presented in both preparations.
According to the present invention, " storage is stable " or " bin stability " is represented at the standard conditions (in room temperature and general wet At least 2 years under degree), the difference of active compound content and initial amount in pharmaceutical formulation be no more than general pharmacopeia explanation or Numerical value shown in guilding principle.According to the present invention, bin stability also refers to preparation prepared in accordance with the present invention can be in standard conditions Under (60% relative humidity, 25 DEG C) store, as obtain listing license needed for condition.
According to the present invention, after " storage stabilization " or " time stabilization " also illustrates that storage at the standard conditions, activity The release mode that compound is presented is not stored with the compound i.e. thirty years of age use.It is relevant according to the present invention, release mode Acceptable variation characteristic is that the burst size change of time per unit is no more than 20% relative to average value, preferably more than 15%, and particularly preferably it is no more than 10%.Average value is calculated by six measured values of release mode.
Preferably, according to blue (Basket Method) method of the medicine of American Pharmacopeia (USP), in pH=1.2 or pH=6.5 The release in reactive compound self-sustaining release formulation is determined using HPLC.
The measure of bin stability is carried out preferably according to USP medicine basket method in pH=1.2, using HPLC.
According to the present invention, " non-expandable (non-swellable) " or " substantially non-expandable " diffusion matrix are A kind of matrix formulations, the release of reactive compound are not expanded (especially in related target position in patient body by the matrix In physiological fluid) influence (or at least certain degree is unaffected).
According to the present invention, " substantially non-expandable " diffusion matrix also refers to a kind of matrix, and its volume is (outstanding in the aqueous solution It is in patient body in the physiological fluid of related target position) it will increase about 300%, preferably from about 200%, more preferably from about 100%, About 75% or about 50%, even more preferably about 30% or about 20%, and most preferably from about 15%, about 10%, about 5% or about 1%.
In the technology contents of the present invention, " activator " or " anodyne " always refers to dihydrohydroxycodeinone.In the technology of the present invention Rong Zhong, " antagonist " always refer to naloxone.
Preparation prepared in accordance with the present invention can orally, intranasal, per rectum and/or pain therapy is applied to by suction. According to the present invention, parenteral is not contemplated.The formula of particularly preferred oral administration.
Although and it is unspecified, term " activator " or " antagonist " always include pharmaceutically acceptable and equivalent effect derivative Thing, salt etc..If for example, refer to dihydrohydroxycodeinone or naloxone, in addition to free alkali, in addition to its hydrochloride, sulfate, Disulfate, tartrate, nitrate, citrate, biatrate, phosphate, malate, maleate, hydrobromic acid Salt, hydriodic acid salt, fumarate, succinate etc..
According to the present invention, activator and antagonist are prepared in the following manner：Make both in a manner of lasting, independent and be stable By being discharged in obtained pharmaceutical preparation.This is not meant to that antagonist is more excessive than activator.On the contrary, containing activator/short of money In the formula of the combination of anti-agent (it shows the release mode according to the present invention), preferably activator is more excessive than antagonist.
The excess of activator is depending on the content of the unit dose of antagonist in combination preparation.The mistake of class opioid agonist Amount degree is generally represented with activator relative to the weight ratio of antagonist.
In the case of dihydrohydroxycodeinone and naloxone, activator is being up to 25 relative to the preferred weight ratio of antagonist:1 Weight ratio in the range of, particularly weight than scope be 15:1、10:1、5:1、4:1、3:1、2:1 and 1:1.
The absolute content of used activator and antagonist depends on the selection of reactive compound., must according to the present invention Specifically activator and antagonist are in a manner of independent and be stable, are released by the pharmaceutical preparation for being prepared into stable release Put.
If allocating combination preparation using dihydrohydroxycodeinone and naloxone, per unit dose preferably comprises 10 to 150mg, more 10 are preferably comprised to 80mg dihydrohydroxycodeinones (typical doses of application), and preferably comprises 1 to 50mg naloxones.
In other preferred embodiments of the present invention, said preparation can contain 5 to 50mg dihydrohydroxycodeinones, 10 to 40mg hydroxyl hydrogen Ketone, 10 to 30mg dihydrohydroxycodeinones or about 20mg dihydrohydroxycodeinones can be treated.The preferred embodiments of the invention may also comprise every list Position dosage has 1 preparation to 40mg naloxones, 1 to 30mg naloxones, 1 to 20mg naloxones or 1 to 10mg naloxones.
According to the present invention, the ratio of selection dihydrohydroxycodeinone and naloxone, it is necessary to assure obtain two kinds according to the present invention The release mode of active material, and activator can play its analgesic efficacy；And take can reduce or eliminate the custom of activator into Property or the mode of habituation enhancement effect and side effect select the dosage of antagonist, but (not substantial) analgesic for influenceing activator Effect.According to the present invention, form the habit and habituation, and intractable constipation and respiratory depression, all it is considered as with analgesic effect The side effect of class opioid agonist.
According to the present invention, generally conventional formula can be used, as long as these formulas can ensure that reactive compound with lasting, only Vertical and stable mode discharges from said preparation.According to the present invention, it is necessary to which selection can allow reactive compound to store stable formula.
It is preferred that it is formulated using the retardance (retardation) based on matrix (Matrix-based), as offer according to this The activator of invention and the formula of antagonist release.According to the present invention, particularly preferably based on substantially non-expansiveness diffusion base The formula of matter.Now, preferably there is no the formula of corrosivity matrix or expandable diffusion matrix.
According to the present invention, it is necessary to which selection can provide the matrix of reactive compound sustained release, hold the reactive compound Continuous, independent and stable mode discharges.It is preferred that such a matrix contains the polymer based on ethyl cellulose, and ethyl cellulose is Particularly preferred polymer.Particularly preferably containing commercially available trade namePolymer matrix.Particularly preferably UseE-7-7050。
Formula with release behavior of the present invention particularly including following matrix, the matrix contain ethyl cellulose and at least one Kind fatty alcohol is as the component for substantially influenceing the matrix release characteristics.The content of ethyl cellulose and at least one fatty alcohol can It is significantly different, it can so obtain the preparation with different release modes.Although (inventive) preparation of innovation usually contains Two kinds of components are stated, in some cases, preferred formulation comprises only ethyl cellulose or fatty alcohol as the component for determining release.
According to the present invention, it is presently preferred to avoid following matrix：Based on polymethacrylates matrix (for example,RS30D andRL30D) or the matrix containing appropriate water-expandable material, especially hydroxyalkyl are fine Tie up plain derivative, such as HPMC.
Release of active compounds and often can be used to produce in a manner of lasting, independent and be stable according to the matrix of the present invention Unit interval discharges the preparation of equivalent amount of active compound.Specifically refer to, just the hydroxyl containing 12mg dihydrohydroxycodeinones and 4mg naloxones For hydrogen can treat ketone/naloxone combination, release 25% treats ketone and 25% hydroxypropyl Oxymorphone in initial 4 hours；Phase Ying Di, for the dihydrohydroxycodeinone containing 24mg dihydrohydroxycodeinones and 8mg naloxones/naloxone combination, in initial 4 hours The dihydrohydroxycodeinone and 25% naloxone of release 25%；Change in the case of this two kinds be no more than average value (now for 25% dihydrohydroxycodeinone or naloxone) 20%.
From the aspect of career in medicine medicine, it is preferable that two kinds of reactive compounds, which have this identical release behavior,.
The preferred embodiments of the invention be on release 1% to 40% after 15 minutes, preferably 5% to 35%, it is more excellent Select the preparation of 10% to 30%, further preferred 15% to 25% dihydrohydroxycodeinone and/or the preparation of naloxone.The present invention's In other preferred embodiments, 15% to 20%, 20% to 25%, about 15%, about 20% or about 25% dihydrohydroxycodeinone and/ Or naloxone discharged after 15 minutes.
Another preferred embodiment of the present invention be on after 1 hour, release 25% to 65%, preferably 30% to 60%th, more preferably 35% to 55%, particularly preferred 40% to 50% dihydrohydroxycodeinone and/or the preparation of naloxone.The present invention Preferred embodiment be directed to 40% to 45%, 45% to 50%, about 40%, about 45% or about 50% dihydrohydroxycodeinone And/or the preparation of naloxone release after 1 hour.
The another preferred embodiment of the present invention be on after 2 hours, release 40% to 80%, preferably 45% to 75%, More preferably 45% to 70%, further preferred 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65% or 65% To 70% dihydrohydroxycodeinone and/or the preparation of naloxone.Preferred embodiment also include about 45%, about 50%, about 55%, about 60%th, the preparation of about 65% or about 70% dihydrohydroxycodeinone and/or the naloxone release after 2 hours.
The preferred embodiment of the present invention be on after 4 hours, release 70% to 100%, preferably 75% to 95%th, more preferably 80% to 95%, further preferred 80% to 90% dihydrohydroxycodeinone and/or the preparation of naloxone.This hair The hydroxyl hydrogen that bright preferred embodiment is directed to 80% to 85%, 85% to 90%, about 80%, about 85% or about 90% can be treated The preparation of ketone and/or the naloxone release after 4 hours.
The present invention a preferred embodiment be directed to after 7 hours, release 70% to 100%, preferably 75% to 100%th, more preferably 80% to 95%, further preferred 80% to 85%, 85% to 90% or 90% to 95% hydroxyl hydrogen can be treated The preparation of ketone and/or naloxone.The preferred embodiments of the invention are directed to about 80%, about 85%, about 90% or about 95% The preparation of dihydrohydroxycodeinone and/or the naloxone release after 7 hours.
Another of the invention preferred embodiment be on after 12 hours, release 85% to 100%, preferably 90% to 100%th, more preferably 95% to 100%, further preferred about 95% or 100% dihydrohydroxycodeinone and/or the preparation of naloxone.
According to the present invention, there is provided the formula of release of active compounds according to the present invention, the polymer except forming matrix Outside, it can also contain filler and additive, such as granulating aids, lubricant, colouring agent, flowable and plasticizer.
Lactose, glucose or sucrose, starch and its hydrolysate, microcrystalline cellulose, cellulose (cellatose), mountain The glycitols such as pears sugar alcohol or mannitol, more dissolubility calcium salts such as calcium monohydrogen phosphate, Dicalcium Phosphate or tricalcium phosphate, can be used as Filler.
PVP (povidone) can be used as granulating aids.
It is preferred that use high dispersion silicaTalcum powder, cornstarch, magnesia and magnesium stearate are hard Resin acid calcium is as flowable or lubricant.
Magnesium stearate and/or calcium stearate preferably are used as lubricant, it also may be preferable for (such as hard using fatty acid Resin acid) or fats (such as rilanit special).
Polyethylene glycol and fatty alcohol [such as cetanol, and/or stearyl alcohol, and/or the mixing of hexadecanol octadecyl alcolol can also be used Thing (cetostearylalcohol)], as the additive for influenceing retardation (retardation).
If using filler and additive, such as colouring agent and above-mentioned lubricant, flowable and plasticizer, then must be noted that Arrive, according to the present invention, only using the combinations thereof and base of the release mode for ensureing to obtain the reactive compound according to the present invention Matter forming material and/or matrix former matter.
Formula all supplementary elements with can allow release matrix obtain it is a kind of substantially it is non-aqueous expansion or non-buffered liquid expand (non-buffer-swellable) and the mode of characteristic of the matrix of non-aggressive diffusion is selected.
According to the present invention, formula particularly preferably containing ethyl cellulose orE-7-7050 constructs as matrix Material, stearyl alcohol aid in as lubricant, lactose as fatty alcohol, magnesium stearate as filler, and PVP as granulation Agent.
According to the present invention, any common administration form can be made in formula, and in principle, this administration form is adapted to retardance to match somebody with somebody Side simultaneously ensures that reactive compound discharges in the manner of the present invention.Especially suitable person is tablet, multilayer tablet and capsule.It can be used His administration form, such as granule or pulvis, but only it is provided with enough retardations and the use of the release behavior according to the present invention Medicine form is acceptable.
Pharmaceutical preparation may also comprise film coating.However, it is necessary to ensure that the film coating will not negatively affect active ingredient The property that thing discharges from matrix, and bin stability of the reactive compound in matrix.Such a film coating can dye, or If necessary, the priming dose containing reactive compound.The reactive compound of the priming dose will discharge at once, so can be non- Often rapidly reach therapeutically effective plasma concentration.
Using cumulative formula (build-up) or cut down medicine of formula (build-down) comminution granulation manufacture according to the present invention Preparation or its predecessor.Preferred embodiment is using mist projection granulating and the preparation method for being subsequently dried particle.Another side of being preferable to carry out Case is in roller or is granulated on disk, and particle is manufactured by using cumulative formula comminution granulation.Then suitable additive and side are utilized The particle is pressed into such as tablet by method.
Granulating technique of those skilled in the art's applications well known on pharmaceutical technology.Embodiment (see below) discloses this hair Bright specific embodiment.However, changing the parameter of the preparation method for specific purpose to be reached, this is in art technology Within the category that personnel can fully understand.
According to the present invention, the method using extruding (extrusion) technology manufacture pharmaceutical preparation or its predecessor especially has Profit.In a preferred embodiment, using extrusion manufacture pharmaceutical preparation or its predecessor is melted, it is in the same direction using being equipped with Or counter-rotational squeezer (including two screw rods (screw)).Another preferred embodiment is the method by extruding manufacture, It utilizes the squeezer containing one or more screw rods.These squeezers may also comprise kneading member.
Extrusion is also a kind of production method fully established on pharmaceutical technology, is known to the skilled person. Those skilled in the art can fully understand, in order to produce the product with required characteristic, can change in recipe respectively in extruding Kind parameter, such as charging rate, rotary speed, the heating-up temperature (if if can accomplishing) in different squeezer regions, water content Deng.Embodiment part provides the various embodiments of the preparation according to the present invention, and it is using made from extrusion.
Above-mentioned parameter will be determined by the Special Category of used squeezer.In extrusion process, (present invention matches somebody with somebody for heating zone Side component in wherein melt) temperature can be 40 to 120 DEG C, preferably 50 to 100 DEG C, more preferably 50 to 90 DEG C, further It is preferred that 50 to 70 DEG C, most preferably 50 to 65 DEG C, especially with rotating backward double-screw extrusion device (such as Leistritz Micro 18GGL) situation.Those skilled in the art can fully understand that not each heating zone must heat.Especially It is behind feeder (component is mixed into part), it may be necessary to be cooled to about 25 DEG C.Rotary speed can be per minute 100 To 500 rotations (rpm), preferably 100 to 250rpm, more preferably 100 to 200rpm and most preferably from about 150rpm, particularly make With the situation for rotating backward double-screw extrusion device (such as Leistritz Micro 18GGL).The geometrical configuration and diameter of nozzle Selected needed for visual.The nozzle diameter of conventional squeezer is typically 1 to 10mm, preferably 2 to 8mm, most preferably 3 to 5mm.Can For producing the squeezer of invention formulation, its screw rod (screw) length ordinarily be about 40 relative to the ratio of diameter:1.
In general, the temperature of heating zone must be selected, will not produce the temperature for destroying the pharmaceutically active compound Degree.Selection charging rate is extruded with rotary speed by making pharmaceutically active compound be utilized certainly in a manner of lasting, independent and be stable Preparation release obtained by method, and the pharmaceutically active compound can stablize storage in matrix.If for example, increase charging rate, Then rotary speed must relatively be increased to ensure that to obtain identical retardation.
Those skilled in the art will know that above-mentioned whole parameters all depend on special producing condition, (squeezer species, spiral are several What configuration, quantity of component etc.), it may be necessary to changed, so as to be provided by preparation made from extrusion lasting, only Vertical and stable release, and above-mentioned bin stability.
Those skilled in the art can be deduced by embodiment (see below), by changing the parameter in extrusion process, and Change the component relationship of the compound of the release behavior essentially responsible for said preparation, the system with different release modes can be obtained Agent.Therefore the present invention allows the preparation for preparing the release mode with required dihydrohydroxycodeinone and naloxone first, for example, passing through Change fatty alcohol or matrix forms the content of polymer ethyl cellulose, and preparation parameter, such as temperature, rotary speed (are squeezed During pressure) or manufacture tablet during pressure.
Once obtaining with the preparation for being intended to release mode, then art technology can be allowed according to the innovation preparation of the present invention Personnel change in said preparation in the content of the reactive compound listed above.Containing different amounts of reactive compound but with real The preparation of same composition in matter, it will can provide characteristic that is lasting, stable and independently discharging.
Therefore, embodiment part discloses various embodiments, it was demonstrated that can be obtained by changing dosage (such as ethyl cellulose) To the preparation with different release modes.Other embodiment confirms that once establishing a certain preparation has desired release mode, If the content difference of reactive compound is substituted by pharmaceutical active excipient (such as lactose), change the content not shadow of naloxone Ring the release behavior of said preparation.
Brief description of the drawings
Fig. 1：The screw geometry construction of squeezer；
Fig. 2：The rate of release of the dihydrohydroxycodeinone of different content；
Fig. 3 A-B：The release of dihydrohydroxycodeinone, naloxone under different pH；
Fig. 4 A-B：Containing tilidine and naloxoneThe release of the composition of tablet；
Fig. 5 A：The sweep electron microscope photo of Ox/Na1-10- tablets, amplify 25 times；
Fig. 5 B：The sweep electron microscope photo of Ox/Na1-10- tablets, amplify 200 times；
Fig. 6 A：The sweep electron microscope photo of Oxy/Na1-Extr- tablets, amplify 40 times；
Fig. 6 B：The sweep electron microscope photo of Oxy/Na1-Extr- tablets, amplify 100 times；
Fig. 7 A：The sweep electron microscope photo of N- tablets, amplify 25 times；
Fig. 7 B：The sweep electron microscope photo of N- tablets, amplify 100 times.
Embodiment
The embodiment for showing the extremely advantageous embodiment of the present invention is shown in hereafter.Also other embodiment checking is provided originally The advantages of preparation of invention relatively descends with common recipe ratio.The possibility that these embodiments should not be construed as limiting the present invention is implemented Scheme.
Embodiment 1：Produced in non-expansiveness diffusion matrix and contained using spray granulation (spray granulation) The tablet of different amounts of dihydrohydroxycodeinone/naloxone
The constituent content that following table is listed is used for preparing dihydrohydroxycodeinone/naloxone tablet according to the present invention.
It is usedE-7-7050 polymeric blends have following composition.
For tablet to be prepared, mixing dihydrohydroxycodeinone hydrochloride, naloxone hydrochloric acid in rolling type agitator (Bohle) Salt, PVP 30 and lactose Flow Lac 100, then used in fluidized bath prilling granulator (GPCG3)E-7- 7050 progress are spray-granulated.This raw material is sieved by Comill 1.4mm screen clothes.In strength cutting agitator (Collette) In with the fatty alcohol of melting carry out another granulation step.There is 123mg weight (by dry by whole labels made from the above method Object amount meter).
Embodiment 2：Using extrusion production in non-expansiveness diffusion matrix containing dihydrohydroxycodeinone and naloxone Tablet
The constituent content that following table is listed is the tablet for manufacturing dihydrohydroxycodeinone/naloxone according to the present invention.
Preparation (title) Oxy/Na1-Extr
Dihydrohydroxycodeinone hydrochloride 20mg
Naloxone hydrochloride 10mg
Kollidon 30 6mg
Lactose Flow Lac 100 49.25mg
Ethyl cellulose 45cpi 10mg
Stearyl alcohol 24mg
Talcum powder 2.5mg
Magnesium stearate 1.25mg
Upper table is listed to dihydrohydroxycodeinone hydrochloride, ethyl cellulose 45cpi, PVP 30, stearyl alcohol and the breast of dosage Sugared Flow Lac 100 are mixed in rolling type agitator (Bohle).Followed by rotating backward double-screw extrusion device, model Micro 18GGL (Leistritz AG, Nurnberg, Germany), extrude the mixture.The temperature of heating zone 1 is 25 DEG C, heating The temperature in area 2 is 50 DEG C, and the temperature of heating zone 3 to 5 is 60 DEG C, and the temperature of heating zone 6 to 8 is 55 DEG C, and the temperature of heating zone 9 is 60 DEG C, the temperature of heating zone 10 is 65 DEG C.Screw rotation speed is 150 turns (rpm) per minute, and the melting temperature of gained is 87 DEG C, charging rate is 1.5kg/h, and the diameter of nozzle opening is 3mm.Raw material through extruding is with 0.68 × 1.00mm's of Frewitt Screen cloth sieves.Then (it is in advance by being added to 1mm hands sieve for the extrudate after mixing milling and talcum powder and magnesium stearate Processing on net), it is subsequently compressed into tablet.Squeezer has screw geometry construction, as shown in Figure 1.
With it is same contain withBased on (- based) non-expansiveness diffusion matrix but Dihydrohydroxycodeinone/naloxone the tablet produced using spray granulation (referring to embodiment 1) is compared, and the preparation of extruding contains less Component.
Embodiment 3：The release mode of dihydrohydroxycodeinone made from embodiment 1/naloxone tablet
In pH=1.2, using HPLC according to the release of USP medicine blue party method after the reactive compound of measurement in 12 hours. Test tablet Ox/Nal-0, Ox/Nal-5 and Ox/Nal-10.
It can confirm that one is true by Fig. 2 and following listed numerical value, be based onNon- expansiveness diffusion matrix and Speech, the rate of release of the dihydrohydroxycodeinone of different content are remained to maintain identical (stabilization), not influenceed by naloxone content.Accordingly Ground, in dihydrohydroxycodeinone content difference, also observe that naloxone has stable release mode.
Release numerical value is related to dihydrohydroxycodeinone or naloxone (the 2nd row), and it is as a percentage.For example, naloxone in The release average value of 420 minutes is 92.7%.Maximum deviation in 420 minutes is 1%.Oxy and Na1 represents that hydroxyl hydrogen can be treated respectively Ketone and naloxone, and indicate determined reactive compound.
Embodiment 4：Dihydrohydroxycodeinone made from embodiment 2/naloxone tablet is in the release mode of different pH value
Reactive compound is to be measured in pH=1.2 after 12 hours from the release of tablet；Or in pH=1.2 after 1 Hour measurement, then measured in pH=6.5 after 11 hours.According to USP medicine basket method, release speed is determined using HPLC Rate.
Following rate of release is to be measured in pH=1.2 after 12 hours.
The rate of release of following table is to be measured in pH=1.2 after 1 hour, and in pH=6.5 after measurement in 11 hours.
Release numerical value is related to dihydrohydroxycodeinone or naloxone (the 2nd row), and it is as a percentage.Oxy and Na1 difference tables Show dihydrohydroxycodeinone and naloxone, and indicate determined reactive compound.
The form of embodiment 4 is compared with the numerical value in the form of embodiment 3, clearly learns that reactive compound is made by oneself with equivalent Agent discharges, and is not influenceed by preparation method.For example, at 420 minutes, 89.4% dihydrohydroxycodeinone self-spray granulation type tablet is released Put (Ox/Na1-10- tablets, referring to embodiment 3), and at 420 minutes, the hang oneself tablet of extruding of 92.9% dihydrohydroxycodeinone is released Put (Oxy/Na1-Extr-1.2-O, embodiment 4).The numerical value and dihydrohydroxycodeinone of dihydrohydroxycodeinone self compaction matrix agent release Average value (at 420 minutes, the 91.9%) difference 1.1% of self-spray granulation type tablet release.At 420 minutes, 93.5% receives The tablet release (Ox/Na1-10- tablets, referring to embodiment 3) that Lip river ketone self-spray is granulated, and at 420 minutes, 93.9% Na Luo The agent of ketone self compaction matrix discharges (Ox/Na1-Extr-1.2-O, embodiment 4).The agent of naloxone self compaction matrix release numerical value, with Average value (at 420 minutes, the 92.7%) difference 1.3% of alkene Naloxone self-spray granulation type tablet release.
Furthermore by the form of embodiment 4 numeric ratio compared with and Fig. 3 a and 3b it is inferred that rate of release is not influenceed by pH, The release of dihydrohydroxycodeinone, naloxone remains identical and stably.
Embodiment 5：Comparative Example：The release behavior of tablet
The situation that active material during inspecting 7 hours discharges from tablet.According to USP medicine basket method, surveyed in pH=1.2 It is fixedTablet 1 hour, should then using HPLC in other re-tests of pH=6.5 6 hoursTablet contains 50mg tilidines and 4mg naloxones (Ti/Na1-50/4) contain 100mg tilidines and 8mg naloxones (Ti/Na1-100/ 8) or 150mg tilidines and 12mg naloxones (Ti/Na1-150/12) are contained.
Numerical value [just expand by expandable (and being probably corrosivity) with appropriate HPMC as shown in Fig. 4 A and 4B and following table For scattered matrix] to know, the release situation of the tilidine of different content is significantly different, and the release feelings of the naloxone of different content Shape is not stable.This is applied to naloxone.This is represented in the pH, the release situation of reactive compound not mutually independent of 's.
Release numerical value is related to tilidine or naloxone (the 2nd row), and it is as a percentage.The release of naloxone is averaged Value, such as be 78.87% when 420 minutes.Maximum deviation in 420 minutes is 20.4%.Ti1 and Na1 represents that pain is vertical respectively Fixed and naloxone, and indicate determined reactive compound.
Embodiment 6：Using electron microscope carry out embodiment 1 and 2 tablet withThe structure of N tablets compares.
In order to carry out electron microscope, using the tablet containing 20mg dihydrohydroxycodeinones and 10mg naloxones, this tablet leads to The spray granulation for crossing embodiment 1 prepares (Ox/Na1-10) or prepared (Oxy/Na1-Extr) by the extrusion of embodiment 2. Furthermore using containing 100mg tilidines and 8mg naloxonesN tablets.Fig. 5 A and 5B show Ox/Na1-10- pieces The different amplification of the sweep electron microscope photo of agent, the tablet contain inventive formulation, and are to utilize mist projection granulating It is prepared by method.Fig. 6 A and 6B show the different amplification of the sweep electron microscope photo of Oxy/Na1-Extr- tablets, the piece Agent contains inventive formulation, and is prepared using extrusion.Fig. 7 A and 7B are shownThe scanning electron of N- tablets shows Micro mirror photo.
By the comparison of these diagrams, it can be seen clearly that, the tablet containing inventive formulation has substantially more careful And compare the surface of homogeneous texture, thanThe slight crack of tablet is less, no matter the tablet whether be with spray granulation or Extrusion production.Difference in structure may be exactly that different preparations have the reason for different release behaviors.
Embodiment 7：Produced in non-expansiveness diffusion matrix using extrusion and contained containing different dihydrohydroxycodeinone/naloxones The tablet of amount
The constituent content that following table is listed is for producing dihydrohydroxycodeinone/naloxone tablet according to the present invention.
(embodiment 2) carries out extrusion as described above, using following parameters：
OxN20/1-Extr-A：Temperature：55-63℃
Rpm (rotating speed (screw))：150rpm
Charging rate：1.5kg/h
OxN20/1-Extr-B：Temperature：55-63℃
Rpm (rotating speed)：155rpm
Charging rate：1.5kg/h
OxN20/1-Extr-C：Temperature：55-63℃
Rpm (rotating speed)：1505rpm
Charging rate：1.5kg/h
OxN20/10-Extr-A：Temperature：55-63℃
Rpm (rotating speed)：160rpm
Charging rate：1.75kg/h
Tablet manufacturing is carried out using common sheet devices of beating, using following parameters：
OxN20/1-Extr-A：rpm：40rpm
Pressure：9kN
OxN20/1-Extr-B：rpm：42rpm
Pressure：8.9kN
OxN20/1-Extr-C：rpm：36rpm
Pressure：9kN
OxN20/10-Extr-A：rpm：36rpm
Pressure：7.5kN
Using USP medicine basket method, releases of the HPLC after 12 hours measurement reactive compounds is used in pH=1.3.Survey Following tablet formulations are tried：OxN20/1-Extr-A, OxN20/1-Extr-B, OxN20/1-Extr-C and OxN20/10-Extr-A.
From numerical value listed in Table, for the non-expansiveness diffusion matrix based on ethyl cellulose, no Substantially remain identical with the rate of release of the naloxone of content, do not influenceed by dihydrohydroxycodeinone content.Accordingly, these Preparation provides the independence of the reactive compound and stable release.
Release numerical value is related to dihydrohydroxycodeinone or naloxone (the 2nd row), and it is as a percentage.The release of naloxone is put down Average, such as be 92.3% when 420 minutes.Maximum deviation in 420 minutes is 7.4%.Oxy and Na1 represents hydroxyl hydrogen respectively Ketone and naloxone can be treated, and indicates determined reactive compound.
Therefore, once the preparation development be intended to release mode comes out, then the content of the reactive compound can be changed, But the release mode of reactive compound is not significantly changed.Preparation containing different amounts of reactive compound stills provide one kind and held Continuous, independent and stable release.
Embodiment 8：The tablet containing dihydrohydroxycodeinone/naloxone in non-expansiveness diffusion matrix is produced using extrusion
The following example shows, using the formula of the present invention, can be made containing dihydrohydroxycodeinone and naloxone and with spy The preparation of other release behavior.
The content that following table lists component is the tablet for producing dihydrohydroxycodeinone/naloxone according to the present invention.
(embodiment 2) carries out extrusion as described above, using following parameters：
OxN20/1-Extr-D：Temperature：55-63℃
Rpm (rotating speed)：150rpm
Charging rate：1.5kg/h
OxN20/1-Extr-E：Temperature：55-63℃
Rpm (rotating speed)：150rpm
Charging rate：1.5kg/h
OxN20/10-Extr-B：Temperature：55-63℃
Rpm (rotating speed)：160rpm
Charging rate：1.75kg/h
OxN20/10-Extr-C：Temperature：55-63℃
Rpm (rotating speed)：160rpm
Charging rate：1.75kg/h
OxN20/10-Extr-D：Temperature：55-63℃
Rpm (rotating speed)：150rpm
Charging rate：1.5kg/h
OxN20/10-Extr-E：Temperature：55-63℃
Rpm (rotating speed)：150rpm
Charging rate：1.5kg/h
Tablet manufacturing is carried out using common preforming device, using following parameters：
OxN20/1-Extr-D：rpm：39rpm
Pressure：11kN
OxN20/1-Extr-E：rpm：39rpm
Pressure：10.5kN
OxN20/10-Extr-B：rpm：36rpm
Pressure：9.5kN
OxN20/10-Extr-C：rpm：36rpm
Pressure：7.8kN
OxN20/10-Extr-D：rpm：39rpm
Pressure：9kN
OxN20/10-Extr-E：rpm：39rpm
Pressure：7.5kN
Using USP medicine basket method, in pH=1.2, releases of the HPLC after 12 hours measurement reactive compounds is used.Survey Following tablet formulations are tried：OxN20/1-Extr-D、OxN20/1-Extr-E、OxN20/10-Extr-B、OxN20/10-Extr-C、 OxN20/10-Extr-D and OxN20/10-Extr-E.
Release numerical value is related to dihydrohydroxycodeinone or naloxone (the 2nd row), and it is as a percentage.Oxy and Na1 difference tables Show dihydrohydroxycodeinone and naloxone, and indicate determined reactive compound.
This embodiment confirms, if being to be used as the substantial release characteristics for influenceing said preparation by the use of ethyl cellulose and fatty alcohol Matrix components, then it can produce the preparation with specific release mode.Once the preparation with required release characteristics is made, then can change Become the content of reactive compound.Said preparation will still provide lasting, independent and stable release behavior (referring to embodiment 7).
In summary, the present invention relates to following technical scheme：
A kind of 1. stable pharmaceutical preparation of storage containing dihydrohydroxycodeinone and naloxone, it is characterised in that the activation Compound is to be discharged in a manner of lasting, stable and independent from said preparation.
2. the preparation described in technical scheme 1, it is characterised in that dihydrohydroxycodeinone and/or naloxone are with pharmaceutically acceptable and equal work Property derivative form exist, the derivative is such as free alkali, salt.
3. the preparation described in technical scheme 2, it is characterised in that dihydrohydroxycodeinone and/or naloxone with their hydrochloride, Sulfate, disulfate, tartrate, nitrate, citrate, biatrate, phosphate, malate, maleate, Hydrobromate, hydriodate, the form of fumarate or succinate are present.
4. the preparation in above-mentioned technical proposal described in any one, it is characterised in that the amount of dihydrohydroxycodeinone exceedes naloxone Unit dose.
5. the preparation in above-mentioned technical proposal described in any one, it is characterised in that the dosage of naloxone is 1 to 50mg.
6. the preparation in above-mentioned technical proposal described in any one, it is characterised in that the dosage of dihydrohydroxycodeinone be 10 to 150mg, preferably 10 to 80mg.
7. the preparation in above-mentioned technical proposal described in any one, it is characterised in that the weight of dihydrohydroxycodeinone and naloxone It is up to 25 than scope:1, preferably at most 20:1、15:1, particularly preferred 5:1、4:1、3:1、2:1 or 1:1.
8. the preparation in above-mentioned technical proposal described in any one, it is characterised in that said preparation contains substantially non-inflatable Property and noncorrosive diffusion matrix.
9. 8 preparation described in technical scheme, it is characterised in that the diffusion matrix at least contains ethyl cellulose and at least one Kind fatty alcohol is as the substantial component for influenceing release active compound behavior.
10. the preparation described in technical scheme 8 or 9, it is characterised in that said preparation does not contain corresponding alkali and/or water and may expand Material, especially acrylic acid derivative and/or hydroxyalkyl cellulose derivative.
11. the preparation in above-mentioned technical proposal described in any one, it is characterised in that said preparation contain Conventional filler and Additive, especially lubricant, flowable and plasticizer etc..
12. the preparation described in technical scheme 11, it is characterised in that said preparation contains magnesium stearate, calcium stearate and/or the moon Cinnamic acid calcium and/or aliphatic acid are as lubricant, preferably stearic acid.
13. the preparation described in technical scheme 11, it is characterised in that said preparation contains the silica of high degree of dispersion, preferably height point Property silica is dissipated, talcum powder, cornstarch, magnesia and magnesium stearate and/or calcium stearate are as flowable.
14. a kind of store stable pharmaceutical preparation, said preparation contains hydroxyl hydrogen in substantially non-expansiveness diffusion matrix Ketone and naloxone can be treated, it is characterised in that the substantial release characteristics of the matrix are by ethyl cellulose and at least one fat Alcohol influences, and the weight of dihydrohydroxycodeinone contained by said preparation and naloxone is up to 25 than scope:1, preferably at most 20:1、 15:1, particularly preferred 5:1、4:1、3:1、2:1 or 1:1.
15. the preparation described in technical scheme 14, it is characterised in that dihydrohydroxycodeinone and naloxone are with pharmaceutically acceptable and equal The form of the derivative of activity is present, and the derivative is such as free alkali, salt.
16. the preparation described in technical scheme 15, it is characterised in that dihydrohydroxycodeinone and naloxone with hydrochloride, sulfate, Disulfate, tartrate, nitrate, citrate, biatrate, phosphate, malate, maleate, hydrobromic acid Salt, hydriodate, the form of fumarate or succinate are present.
17. the preparation in technical scheme 14 to 16 described in any one, it is characterised in that the amount of dihydrohydroxycodeinone, which exceedes, to be received The unit dose of Lip river ketone.
18. the preparation in technical scheme 14 to 17 described in any one, it is characterised in that the amount of naloxone is 1 to 50mg.
19. the preparation in technical scheme 14 to 18 described in any one, it is characterised in that the amount of dihydrohydroxycodeinone be 10 to 150mg, preferably 10 to 80mg.
20. the preparation in technical scheme 14 to 19 described in any one, it is characterised in that said preparation contain it is substantially non-can Dilatancy and noncorrosive diffusion matrix.
21. the preparation described in technical scheme 20, it is characterised in that the diffusion matrix is at least containing ethyl cellulose and at least A kind of fatty alcohol is as the substantial component for influenceing release active compound behavior.
22. the preparation described in technical scheme 20 or 21, it is characterised in that said preparation does not contain corresponding alkali and/or water can be swollen Swollen material, especially acrylic acid derivative and/or hydroxyalkyl cellulose derivative.
23. the preparation in technical scheme 14 to 22 described in any one, it is characterised in that the fatty alcohol includes laruyl alcohol, meat Cardanol, stearyl alcohol, cetostearyl alcohol, ceryl alcohol and/or cetanol, particularly preferred stearyl alcohol.
24. the preparation in technical scheme 14 to 23 described in any one, it is characterised in that said preparation contains usual fillers And additive, especially lubricant, flowable, plasticizer etc..
25. 24 preparation described in technical scheme, it is characterised in that said preparation contains magnesium stearate, calcium stearate and/or the moon Cinnamic acid calcium and/or aliphatic acid are as lubricant, preferably stearic acid.
26. 24 preparation described in technical scheme, it is characterised in that said preparation contains the silica of high degree of dispersion, preferably height point Property silica is dissipated, talcum powder, cornstarch, magnesia and magnesium stearate and/or calcium stearate are as flowable.
27. the preparation in above-mentioned technical proposal described in any one, it is characterised in that contain ethyl cellulose with commercially available Polymeric blends, preferablyE-7-7050 replaces ethyl cellulose.
28. the preparation in above-mentioned technical proposal described in any one, it is characterised in that by said preparation be prepared into oral formulations, Nasal formulations, rectum preparation or suction preparation.
29. the preparation in above-mentioned technical proposal described in any one, it is characterised in that said preparation be tablet, pill, capsule, Granule and/or pulvis.
30. the preparation in above-mentioned technical proposal described in any one, it is characterised in that said preparation or its precursor pass through cumulative Formula cuts down the preparation of formula comminution granulation.
31. the preparation in technical scheme 1 or 29 described in any one, it is characterised in that said preparation or its precursor pass through extruding It is prepared by method.
32. the preparation in above-mentioned technical proposal described in any one, it is characterised in that according to admission guidelines, Said preparation (60% relative humidity, 25 DEG C) can be stored at least 2 years under standard conditions.

Claims (10)

1. dihydrohydroxycodeinone or its officinal salt and naloxone or its officinal salt are being prepared for treating dihydrohydroxycodeinone induction Side effect intractable constipation and do not influence a kind of stable oral drugs of storage of the analgesic effect of dihydrohydroxycodeinone substantially Purposes in preparation, wherein the preparation provides continuing for dihydrohydroxycodeinone or its officinal salt and naloxone or its officinal salt Release, and the weight of dihydrohydroxycodeinone or its officinal salt and naloxone or its officinal salt compares scope in wherein described preparation For 5:1 to 1:1.
2. the purposes of claim 1, wherein the preparation amount is 1 to 50mg naloxone or its officinal salt.
3. the purposes of claim 1 or 2, wherein the preparation amount is 10 to 150mg dihydrohydroxycodeinone or its is pharmaceutically acceptable Salt.
4. the purposes in claims 1 to 3 described in any one, wherein dihydrohydroxycodeinone that the preparation contains or its is pharmaceutically acceptable The amount of salt exceedes naloxone or its officinal salt.
5. the purposes in claim 1-3 described in any one, wherein in the preparation dihydrohydroxycodeinone or its officinal salt with The weight of naloxone or its officinal salt ratio is 5:1、4:1、3:1、2:1 or 1:1.
6. the purposes of claim 5, wherein dihydrohydroxycodeinone or its officinal salt and naloxone or its is pharmaceutically acceptable in the preparation The weight ratio of salt is 2:1.
7. the purposes in claim 1 to 6 described in any one, wherein the preparation discharges 1% to 40% after 15 min Dihydrohydroxycodeinone hydrochloride and naloxone hydrochloride, after 1 hour discharge 25% to 65% dihydrohydroxycodeinone hydrochloride And the dihydrohydroxycodeinone hydrochloride and naloxone hydrochloride of naloxone hydrochloride, after 2 hr release 40% to 80%, 4 Hour after release 70% to 100% dihydrohydroxycodeinone hydrochloride and naloxone hydrochloride, after 7 hours discharge 70% to 100% dihydrohydroxycodeinone hydrochloride and naloxone hydrochloride, and the hydroxyl hydrogen of release 85% to 100% can be treated after 12 hours Keto hydrochloride and naloxone hydrochloride, it is measured in pH=1.2 or pH=6.5, using HPLC according to USP medicine basket method.
8. the purposes in claim 1 to 7 described in any one, wherein the preparation is included with hydrochloride, sulfate, hydrogen sulfate Salt, tartrate, nitrate, citrate, biatrate, phosphate, malate, maleate, hydrobromate, hydrogen iodine The dihydrohydroxycodeinone and/or naloxone of hydrochlorate, fumarate or succinate form.
9. the purposes in claim 1 to 8 described in any one, wherein the preparation be tablet, pill, capsule, granule and/ Or pulvis.
A kind of 10. stable oral drugs of storage containing dihydrohydroxycodeinone or its officinal salt and naloxone or its officinal salt Preparation, wherein the preparation provides dihydrohydroxycodeinone or its officinal salt and the sustained release of naloxone or its officinal salt, its Described in preparation dihydrohydroxycodeinone or its officinal salt with the weight of naloxone or its officinal salt be 5 than scope:1 to 1:1.
CN201710521042.3A 2002-04-05 2003-04-04 Pharmaceutical preparation containing dihydrohydroxycodeinone and naloxone Pending CN107669681A (en)

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DE10215131A DE10215131A1 (en) 2002-04-05 2002-04-05 Stable pharmaceutical preparation useful for the treatment of pain, especially severe pain, without causing side-effects comprises oxycodone and naxolone in retarded release formulation
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